Project Summary Most, if not all, fluorinating reagents (electrophilic or nucleophilic) are actually made from hydrogen fluoride (HF). However, the gaseous and corrosive nature of HF excludes it from working laboratories where special equipment and training are not available. The complexes of HF with organic bases like pyridine-HF complex (Olah's reagent) and triethylamine-HF complex have been explored extensively as nucleophilic sources of fluorine, but use of these organic bases reduce the acidity of the system and may interfere with many metal catalysts. So far there is no HF-based nucleophilic fluorination reagent that works well in acid or transition metal catalyzed reactions. Our primary goal is to develop a new generation of HF-based nucleophilic fluorination reagents that is compatible with acids and metal catalysts based on a rational design. The same strategy can also be used for new HX (X = Cl, Br, I)-based halogenation reagents. Hydrogen bonding, rather than an ionic interaction, has been identified as the major interaction between HF and an organic base in complexes such as pyridine-HF (Olah's reagent). To reduce the volatility of an HF complex (make it a liquid or solid at room temperature), we have to use a relatively good hydrogen bonding acceptor (HBA) to complex with HF. Our hypothesis is: a strong (good) hydrogen bonding acceptor is not necessarily a strong base (Brnsted or Lewis base). In this way, a compound that serves as good hydrogen bonding acceptor (better than pyridine or triethylamine), but is less basic, is expected to form a less volatile complex. And due to the low basicity of this HBA, the resulting HBA-HF complex will be compatible with acid catalysts or mediators. In this manner, we may achieve unprecedented reactivity and selectivity in HF-participating reactions. The first part of our research is the preparation of HBA-HX complexes. We are seeking `anomaly' HBAs, that is, good hydrogen bond acceptors but weak Brnsted bases. The quantitative descriptor of hydrogen bond basicity and Brnsted basicity shown in Figure 1 (based on Laurence and co-workers' database of hydrogen-bond basicity) is our primary guideline for the selection of suitable hydrogen bonding acceptors. The nucleophilic fluorination reagents proposed and the methodologies for their use will enable diverse-oriented, stereo- and regio-selective synthesis of fluoroamines, fluorohydrins, fluoroaminoacids, fluorinated aliphatic, alkenes, cyclic and heterocyclic compounds, through new synthetic protocols such as tandem HF-addition-metathesis, HF trapping in cationic cascade reactions, strain-release nucleophilic fluorinations, in-situ electrophilic fluorine formation, Markovnikov and anti-Markovnikov hydrofluorinations. A similar strategy will be used to develop designer-HX based (X = Cl, Br, I) halogenation reagents. One of our reagents (DMPU-HF) is already commercially available, and we will commercialize other newly developed reagents to make our methods available to medicinal chemists worldwide.